摘要
目的 探讨BRAT1基因变异引起的致命性新生儿肌僵直和多灶性癫痫综合征的临床特点.方法 回顾性分析2023年河南省儿童医院收治的2例BRAT1基因变异引起的致命性新生儿肌僵直和多灶性癫痫综合征患儿的临床资料,以"BRAT1基因"、"致命性新生儿肌僵直和多灶性癫痫综合征"、"新生儿癫痫"、"新生儿惊厥"、"婴儿"、"新生儿"、"ethal neonatal rigidity and multifocal seizure syndrome"、"BRAT1"、"RMFSL"、"neonatal-onset genetic epilepsy"、"neonatal convulsion"、"neonatal seizures"、"newborn"、"neonate"为关键词,检索万方数据库、中国知网、维普数据库、中华医学期刊全文数据库、PubMed、Embase、Web of Science、Cochrane Library数据库自建库至2023年8月31日收录的相关文献,与本院2例一起分析该病的临床特点和基因特点.结果 病例1,男,出生时即有四肢僵直,生后出现间断抽搐,苯巴比妥、咪达唑仑、左乙拉西坦联合治疗后抽搐可缓解,但1周后抽搐再次加重,加用妥泰未见好转.随访至5月龄,生长发育落后,需鼻饲喂养,联合抗惊厥药物治疗仍频繁惊厥发作.BRAT1基因外显子5 c.566_567insG(p.D190fs)和外显子9 c.1276C＞T(p.Q426*)复合杂合变异,分别源自父母.病例2,女,生后即呼吸困难、反应差、抽搐,苯巴比妥联合左乙拉西坦治疗后抽搐一度缓解,但1周后抽搐逐渐频繁,加用咪达唑仑未见明显好转,放弃治疗后死亡.BRAT1基因外显子10 c.1395G＞c(p.T465=)纯合变异,父母无异常.共检索到BRAT1基因变异文献39篇,临床资料记录详尽的文献12篇,以致命性新生儿肌僵直及多灶性癫痫为临床表现35例,加上本文2例共37例,男14例,女23例;有随访记录的患儿32例,末次随访年龄2个月～20岁;死亡27例,死亡年龄6d～20岁;临床主要表现为小头畸形、生后出现难治性癫痫发作、四肢僵直;神经影像学以小脑萎缩/发育不全最常见;脑电图以多灶性癫痫样放电最常见;基因检测复合杂合变异15例,纯合变异21例,未明确类型1例.结论 致命性新生儿肌僵直和多灶性癫痫综合征以小头畸形、肌张力高、难治性癫痫为主要表现,预后差,病死率高,BRAT1基因检测可明确诊断.
Abstract
Objective To explore the clinical characteristics of lethal neonatal rigidity and multifocal seizure syndrome caused by BRAT1 gene mutations.Methods Clinical data of 2 cases of fatal neonatal muscle stiffness and multifocal epilepsy syndrome with BRAT1 gene mutations admitted to Henan Children's Hospital in 2023 were retrospectively analyzed.Literature up to August 2023 was searched from Wanfang Database,CNKI,VIP Database,Chinese Medical Journal Network,PubMed,Embase,Web of Science,Cochrane Library Database with the keywords of"BRAT1 gene","lethal neonatal rigidity and multifocal epilepsy syndrome","neonatal epilepsy","neonatal convulsion","neonatal seizures","infant","newborn","BRAT1","RMFSL","neonal onset genetic replication","neonate"in Chinese and English.Clinical and genetic characteristics of these cases were analyzed together with 2 cases from our hospital.Results Case 1,male,had stiffness in his limbs at birth and intermittent convulsions after birth.The convulsions were relieved after treatment with a combination of phenobarbital,midazolam,and levetiracetam.However,after one week,the convulsions worsened again and could not be relieved after treatment with topiramate.The patient was followed up to 5 months old and had delayed growth and development.Nasogastric tube feeding was required,and frequent seizures were still observed despite combined treatment with anticonvulsant drugs.The BRAT1 gene has a compound heterozygous variation in exon 5 c.566_567insG(p.D190fs)and exon 9 c.1276C＞T(p.Q426*),originating from parents,respectively.Case 2,female,had respiratory distress,poor response,and convulsions after birth.The convulsions improved temporarily after treatment with phenobarbital combined with levetiracetam,but gradually became more frequent after one week.The addition of midazolam did not show significant improvement,and she died after withdraw treatment.The BRAT1 gene has a homozygous variation in exon 10 c.1395G＞c(p.T465=),with no abnormalities observed in the parents.A total of 39 literature on BRAT1 gene mutations were retrieved,with 12 detailed clinical records.Among them,35 cases were clinically characterized by fatal neonatal muscle stiffness and multifocal epilepsy.Together with our two cases,there were 37 patients in total,including 14 males and 23 females.32 patients with follow-up records,with the last follow-up age ranging from 2 months to 20 years old,27 deaths occurred between 6 days and 20 years of age.The main clinical manifestations included microcephaly,refractory epileptic seizures after birth and limb stiffness.Cerebellar atrophy/hypoplasia was the most common neuroimaging manifestation,while multifocal epileptic discharge was the most common feature of in electroencephalography.Genetic test showed 15 cases with compound heterozygous variation and 21 cases with homozygous variation.Conclusions Fatal neonatal muscle rigidity and multifocal epilepsy syndrome are mainly characterized by microcephaly,high muscle tension,and refractory epilepsy,with poor prognosis and high mortality rate.BRAT1 gene testing can provide a clear diagnosis.
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